Skip to Main content Skip to Navigation
Journal articles

Gene‐ and pathway‐level analyses of iCOGS variants highlight novel signaling pathways underlying familial breast cancer susceptibility

Christine Lonjou 1, 2, 3 Séverine Eon‐marchais 1, 2, 3 Thérèse Truong 4 Marie‐gabrielle Dondon 1, 2, 3 Mojgan Karimi 4 Yue Jiao 1, 2, 3 Francesca Damiola 5 Laure Barjhoux 5 Dorothée Le Gal 1, 2, 3 Juana Beauvallet 1, 2, 3 Noura Mebirouk 1, 2, 3 Eve Cavaciuti 1, 2, 3 Jean Chiesa 6 Anne Floquet 7 Séverine Audebert‐bellanger 8 Sophie Giraud 9, 10 Thierry Frebourg 11 Jean‐marc Limacher 12 Laurence Gladieff 13, 14 Isabelle Mortemousque 15 Hélène Dreyfus 16, 17, 18 Sophie Lejeune‐dumoulin 19 Christine Lasset 20, 5 Laurence Venat‐bouvet 21 Yves‐jean Bignon 22, 23 Pascal Pujol 24, 25 Christine Maugard 26 Elisabeth Luporsi 27 Valérie Bonadona 20, 5 Catherine Noguès 28, 29 Pascaline Berthet 30 Capucine Delnatte 31 Paul Gesta 32 Alain Lortholary 33 Laurence Faivre 34, 35, 36 Bruno Buecher 37 Olivier Caron 38 Marion Gauthier‐villars 37 Isabelle Coupier 24, 25 Sylvie Mazoyer 39 Luis‐cristobal Monraz 1, 2, 3 Maria Kondratova 1, 2, 3 Inna Kuperstein 1, 2, 3 Pascal Guénel 4 Emmanuel Barillot 1, 2, 3 Dominique Stoppa‐lyonnet 37, 40 Nadine Andrieu 1, 2, 3 Fabienne Lesueur 1, 2, 3
Abstract : Single-nucleotide polymorphisms (SNPs) in over 180 loci have been associated with breast cancer (BC) through genome-wide association studies involving mostly unselected population-based case-control series. Some of them modify BC risk of women carrying a BRCA1 or BRCA2 (BRCA1/2) mutation and may also explain BC risk variability in BC-prone families with no BRCA1/2 mutation. Here, we assessed the contribution of SNPs of the iCOGS array in GENESIS consisting of BC cases with no BRCA1/2 mutation and a sister with BC, and population controls. Genotyping data were available for 1281 index cases, 731 sisters with BC, 457 unaffected sisters and 1272 controls. In addition to the standard SNP-level analysis using index cases and controls, we performed pedigree-based association tests to capture transmission information in the sibships. We also performed gene- and pathway-level analyses to maximize the power to detect associations with lower-frequency SNPs or those with modest effect sizes. While SNP-level analyses identified 18 loci, gene-level analyses identified 112 genes. Furthermore, 31 Kyoto Encyclopedia of Genes and Genomes and 7 Atlas of Cancer Signaling Network pathways were highlighted (false discovery rate of 5%). Using results from the “index case-control” analysis, we built pathway-derived polygenic risk scores (PRS) and assessed their performance in the population-based CECILE study and in a data set composed of GENESIS-affected sisters and CECILE controls. Although these PRS had poor predictive value in the general population, they performed better than a PRS built using our SNP-level findings, and we found that the joint effect of family history and PRS needs to be considered in risk prediction models.
Document type :
Journal articles
Complete list of metadata

https://hal.archives-ouvertes.fr/hal-03345363
Contributor : Mouniati Colo Connect in order to contact the contributor
Submitted on : Friday, September 17, 2021 - 11:23:43 AM
Last modification on : Wednesday, November 17, 2021 - 12:33:45 PM

File

ijc.33457.pdf
Publication funded by an institution

Licence


Distributed under a Creative Commons Attribution - NonCommercial - NoDerivatives 4.0 International License

Identifiers

Citation

Christine Lonjou, Séverine Eon‐marchais, Thérèse Truong, Marie‐gabrielle Dondon, Mojgan Karimi, et al.. Gene‐ and pathway‐level analyses of iCOGS variants highlight novel signaling pathways underlying familial breast cancer susceptibility. International Journal of Cancer, Wiley, 2021, 148 (8), pp.1895-1909. ⟨10.1002/ijc.33457⟩. ⟨hal-03345363⟩

Share

Metrics

Record views

196

Files downloads

184